The immunoreceptor NKG2D is normally expressed on human CD8+ T cells and NK cells. On pre-activated CD8+ cells, the human NKG2D (hNKG2D) homodimeric receptor functions as a co-stimulator of TCR and CD28+ TCR signalling via its DAP10 association, whereas in NK cells it functions as a direct activator. Various ligands for hNKG2D have been identified and characterized, including the MHC Class I-related ligands MICA and MICB, the UL16-binding protein (ULBP) family, and the retinoic acid early transcript-1 (RAET1) family.
In chronic autoimmune diseases such as rheumatoid arthritis, hNKG2D is expressed on a sub-set of CD4+ CD28− T cells and is involved in stimulation of their proliferation and IFNγ production, and MIC expression is upregulated (Groh et al., PNAS 2003; 100:9452). It has also been shown that CD4+ hNKG2D-expressing T cells in Crohn's disease mediate inflammatory and cytotoxic responses through MICA interactions (Allez et al., Gastroenterology 2007; 132:2346-2358). An initial suggestion that NKG2D is an essential driver in autoimmune inflammation came from the prevention and treatment of the inflammation leading to diabetes in a murine model of diabetes (NOD mice) by a monoclonal antibody (mAb) binding to and blocking murine NKG2D (CX5) (Ogasawara et al., Immunity 2004; 20:757-767), suggesting therapeutic applications for anti-NKG2D antibodies. Such applications have been described in, e.g., US20050158307, WO2005097160, WO2005115517, and WO2006024367.
While murine mAbs against human NKG2D have been described (see, e.g., Pende et al., Eur J Immunol 2001; 31:1076-86, WO02068615; Bauer et al., Science 1999:285:727-9; Castriconi et al., PNAS 2003; 100:4120-25; and André et al., Eur J Immunol 2004; 34:1-11) or are commercially available (e.g., antibody 149810 from R&D Systems, MN, USA, and ON72 from Beckman Coulter Inc.), these are immunogenic. The only fully human anti-NKG2D mAb described in the literature reportedly had both agonistic and antagonistic effects on NKG2D-signalling (Kwong et al., J Mol Biol 2008; 384:1143-1156), rendering it less suitable as a therapeutic agent for inflammatory and/or autoimmune disorders.
Accordingly, there is a need for anti-hNKG2D mAbs with optimal properties for therapeutic use in inflammatory and/or autoimmune diseases and disorders. The present invention addresses these and other needs and provides several additional benefits that will be described in the remainder of this document.